We defined the stem cell profile of K562 line, demonstrating the expression of the Embryonic Transcription Factors Oct3/4, Sox2, Klf4 and Nanog. This profile was associated with a high vulnerability to the physiological oxidizable substrate pyruvate. remarkably, this substrate was shown to be innocuous, even at the highest doses, to normal differentiated cells. This vulnerability is based on a complex metabolic trim centered on the cellular redox state expressed by the NADP/NADPH ratio geared by the mitochondrial respiratory chain. Flow cytometry revealed that the inhibition of this chain by antimycin A produced cell accumulation in the S phase of cell cycle and apoptosis. This block negatively interferes with the aerobic synthesis of purines, without affecting the anaerobic synthesis of pyrimidines. This imbalance was reproduced by using two antifolate agents, LY309887 and raltitrexed (TDX), inhibitors of purine or pyrimidine synthesis, respectively. All this revealed the apparent paradox that low doses of TDX stimulated, instead of inhibiting, leukemia cell growth. This paradox might have significant impact on therapy with regard to the effects of TDX during the intervals of administration, when the drug concentrations become so low as to promote maintenance of dormant cancer cells in hypoxic tissue niches.

The complex metabolic network gearing the G1/S transition in leukemic stem cells: Hints to a rational use of antineoplastic agents / Stivarou, T; Cipolleschi, Mg; D'Amico, M; Mannini, A; Mini, E; Rovida, E; Dello Sbarba, P; Olivotto, M; Marzi, I. - In: ONCOTARGET. - ISSN 1949-2553. - ELETTRONICO. - 6:(2015), pp. 31985-31996. [10.18632/oncotarget.5155]

The complex metabolic network gearing the G1/S transition in leukemic stem cells: Hints to a rational use of antineoplastic agents.

STIVAROU, THEODORA;CIPOLLESCHI, MARIA GRAZIA;D'AMICO, MASSIMO;MANNINI, ANTONELLA;MINI, ENRICO;ROVIDA, ELISABETTA;DELLO SBARBA, PERSIO;OLIVOTTO, MASSIMO;MARZI, ILARIA
2015

Abstract

We defined the stem cell profile of K562 line, demonstrating the expression of the Embryonic Transcription Factors Oct3/4, Sox2, Klf4 and Nanog. This profile was associated with a high vulnerability to the physiological oxidizable substrate pyruvate. remarkably, this substrate was shown to be innocuous, even at the highest doses, to normal differentiated cells. This vulnerability is based on a complex metabolic trim centered on the cellular redox state expressed by the NADP/NADPH ratio geared by the mitochondrial respiratory chain. Flow cytometry revealed that the inhibition of this chain by antimycin A produced cell accumulation in the S phase of cell cycle and apoptosis. This block negatively interferes with the aerobic synthesis of purines, without affecting the anaerobic synthesis of pyrimidines. This imbalance was reproduced by using two antifolate agents, LY309887 and raltitrexed (TDX), inhibitors of purine or pyrimidine synthesis, respectively. All this revealed the apparent paradox that low doses of TDX stimulated, instead of inhibiting, leukemia cell growth. This paradox might have significant impact on therapy with regard to the effects of TDX during the intervals of administration, when the drug concentrations become so low as to promote maintenance of dormant cancer cells in hypoxic tissue niches.
6
31985
31996
Goal 3: Good health and well-being
Stivarou, T; Cipolleschi, Mg; D'Amico, M; Mannini, A; Mini, E; Rovida, E; Dello Sbarba, P; Olivotto, M; Marzi, I
File in questo prodotto:
File Dimensione Formato  
2015 Stivaru et al Oncotarget.pdf

accesso aperto

Descrizione: Articolo principale
Tipologia: Pdf editoriale (Version of record)
Licenza: Creative commons
Dimensione 1.79 MB
Formato Adobe PDF
1.79 MB Adobe PDF Visualizza/Apri

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/1008117
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 7
  • ???jsp.display-item.citation.isi??? 7
social impact